1. Field of the Invention
It is essential for a host that its immune system be responsive to foreign entities especially disease causing pathogens. However, under certain conditions or in specific situations, the immune response may need to be selectively regulated or suppressed. These situations are generally encountered before, during or after organ or bone marrow transplants or to control or treat autoimmune disorders. There are also situations where an uncontrolled immune response triggered by a pathogen or a product could be deleterious for the host, as for example, in the case of septic shock syndrome. The prophylaxis and/or treatment of all such clinical manifestations requires the use of immunosuppressive drugs which can selectively inhibit T cell and/or macrophage responses to specific challenges.
2. Description of the Related Art
In recent years the number of organ transplants including allogenic bone marrow transplants have increased considerably due to their use as a therapeutic option for, inter alia, hematologic, immunologic and malignant disorders. Transplant of bone marrow has led to an immunological complication known as Graft-vs-Host disease (GVHD), where immunologically competent cells of the graft cause damage to the recipient host. This effect is primarily mediated by T lymphocytes (Grebe and Streilein, 1976). Basically, the Major Histocompatibility Complex (MHC) antigens present on all tissue provide the immunological identity to an individual which helps the immune system distinguish between self and non-self so that the immune system can destroy foreign invaders while preserving normal healthy tissue. When MHC bearing tissue is transferred from one individual to another via for example, an organ transplant, it is recognized by the T cell of the recipient as foreign which leads to rejection of tissue in a Host-vs.-Graft (HVG) reaction. However, when MHC bearing immunocompetent cells are transferred from a normal individual to an immunocompromised host (e.g. bone marrow transplant), the grafted immunocompetent cells (mainly T lymphocytes) recognize the differences in host MHC complex and initiate a Graft-vs.-Host reaction leading to GVHD. GVHD is an immunopathophysiologic process with two consecutive phases: the afferent phase, where the recipient tissue first activates the T lymphocytes from the donor and in the second phase (i.e. the effector phase), activated donor cells then secrete inflammatory cytokines, including IL-2 (interleukin 2), IFN-g (interferon g) and TNF-a (tumor necrosing factor a) and recruit additional cells and focus attack on recipient targets. The main targets include the skin, gastrointestinal tract, liver and lymphoid organs (Ferrara and Deeg, 1991). Acute GVHD occurs in approximately 50% of patients who receive bone marrow transplants and is a primary or contributory cause of death in 15-45% of the 50% of the patients who develop GVHD after bone marrow transplant. The post-transplant period is also associated with immune dysfunction due to use of prior ablative radio/chemotherapy to suppress the recipient's lymphoid system (especially mature T lymphocytes) and to allow engraftment of a donor organ (e.g. bone marrow). This in turn often results in severe infections, which are also a major cause of morbidity and mortality in transplant patients. Therapeutic strategy in such situations requires a selective suppression of alloreactivity of T cells and protection against opportunistic infections.